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Please use this identifier to cite or link to this item:
http://ir.nhri.org.tw/handle/3990099045/13812
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| Title: | Alternative splicing mediated by RNA-binding protein RBM24 facilitates cardiac myofibrillogenesis in a differentiation stage-specific manner |
| Authors: | Lu, SH;Lee, KZ;Yeh, YC;Pan, CY;Hsu, PW;Su, LY;Tsai, SY |
| Contributors: | Institute of Molecular and Genomic Medicine |
| Abstract: | Background: Mutations in genes encoding sarcomeric proteins lead to failures in sarcomere assembly, the building blocks of contracting muscles, resulting in cardiomyopathies that are a leading cause of morbidity and mortality worldwide. Splicing variants of sarcomeric proteins are crucial at different stages of myofibrillogenesis, accounting for sarcomeric structural integrity. RNA-binding motif protein 24 (RBM24) is known as a tissue-specific splicing regulator that plays an essential role in cardiogenesis. However, it had been unclear if the developmental stage-specific alternative splicing facilitated by RBM24 contributes to sarcomere assembly and cardiogenesis. Our aim isto study the molecular mechanism by which RBM24 regulates cardiogenesis and sarcomere assembly in a temporal-dependent manner. Methods: We ablated RBM24 from human embryonic stem cells (hESCs) using CRISPR/Cas9 techniques. Results: Although RBM24(-/-) hESCs still differentiated into sarcomere-hosting cardiomyocytes, they exhibited disrupted sarcomeric structures with punctate Z-lines due to impaired myosin replacement during early myofibrillogenesis. Transcriptomics revealed >4000 genes regulated by RBM24. Among them, core myofibrillogenesis proteins (e.g. ACTN2, TTN, and MYH10) were misspliced. Consequently, MYH6 cannot replace non-muscle myosin MYH10, leading to myofibrillogenesis arrest at the early premyofibril stage and causing disrupted sarcomeres. Intriguingly, we found that the actin-binding domain (ABD; encoded by exon 6) of the Z-line anchor protein ACTN2 is predominantly excluded from early cardiac differentiation, whereas it is consistently included in human adult heart. CRISPR/Cas9-mediated deletion of exon 6 from ACTN2 in hESCs, as well as forced expression of full-length ACTN2 in RBM24(-/-) hESCs, further corroborated that inclusion of exon 6 is critical for sarcomere assembly. Overall, we have demonstrated that RBM24-facilitated inclusion of exon 6 in ACTN2 at distinct stages of cardiac differentiation is evolutionarily conserved and crucial to sarcomere assembly and integrity. Conclusions: RBM24 acts as a master regulator to modulate the temporal dynamics of core myofibrillogenesis genes and thereby orchestrates sarcomere organization. |
| Date: | 2022-01-07 |
| Relation: | Circulation Research. 2022 Jan 7;130(1):112-129. |
| Link to: | http://dx.doi.org/10.1161/circresaha.121.320080 |
| JIF/Ranking 2023: | http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0009-7330&DestApp=IC2JCR |
| Cited Times(WOS): | https://www.webofscience.com/wos/woscc/full-record/WOS:000739927500012 |
| Cited Times(Scopus): | https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85123198014 |
| Appears in Collections: | [徐唯哲] 期刊論文
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